This invention relates to compounds which are inhibitors of the interaction between the integrin xcex14xcex21, also known as Very Late Antigen-4 (VLA-4) or CD49d/CD29, and its protein ligands, for example Vascular Cell Adhesion Molecule-1 (VCAM-1) and fibronectin. This invention further relates to processes for preparing such compounds, to pharmaceutical compositions containing them and to their use in methods of therapeutic application.
xcex14xcex21 is a member of the integrin family of heterodimeric cell surface receptors that are composed of noncovalently associated glycoprotein subunits (xcex1 and xcex2) and are involved in cell adhesion to other cells or to extracellular matrix. There are at least 14 different human integrin xcex1 subunits and at least 8 different xcex2 subunits and each , subunit can form a heterodimer with one or more a subunits. Integrins can be subdivided based on their xcex2 subunit composition. xcex14xcex21 is one of several xcex21 integrins, also known as Very Late Antigens (VLA).
The interactions between integrins and their protein ligands are fundamental for maintaining cell function, for example by tethering cells at a particular location, facilitating cell migration, or providing survival signals to cells from their environment. Ligands recognised by integrins include extracellular matrix proteins, such as collagen and fibronectin; plasma proteins, such as fibrinogen; and cell surface molecules, such as transmembrane proteins of the immunoglobulin superfamily and cell-bound complement. The specificity of the interaction between integrin and ligand is governed by the xcex1 and xcex2 subunit composition
Integrin xcex14xcex21 is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils [Hemler, M. E. et al (1987), J. Biol. Chem., 262, 11478-11485; Bochner, B. S. et al (1991), J. Exp. Med., 173, 1553-1556]. Unlike other xcex21, integrins that bind only to cell-extracellular matrix proteins, xcex14xcex21 binds to VCAM-1, an immunoglobulin superfamily member expressed on the cell surface, for example on vascular endothelial cells, and to fibronectin containing the alternatively spliced type III connecting segment (CS-1 fibronectin) [Elices, M. J. et al (1990), Cell, 60, 577-584; Wayner, E. A. et al (1989). J. Cell Biol., 109, 1321-1330].
The activation and extravasation of blood leukocytes plays a major role in the development and progression of inflammatory diseases. Cell adhesion to the vascular endothelium is required before cells migrate from the blood into inflamed tissue and is mediated by specific interactions between cell adhesion molecules on the surface of vascular endothelial cells and circulating leukocytes [Sharar, S. R. et al (1995). Springer Semin. Immunopathol., 16, 359-378]. xcex14xcex21 is believed to have an important role in the recruitment of lymphocytes, monocytes and eosinophils during inflammation. xcex14xcex21/ligand binding has also been implicated in T-cell proliferation, B-cell localisation to germinal centres, haemopoeitic progenitor cell localisation in the bone marrow, placental development, muscle development and tumour cell metastasis.
The affinity of xcex14xcex21 for its ligands is normally low but chemokines expressed by inflamed vascular endothelium act via receptors on the leukocyte surface to upregulate xcex14xcex21 function [Weber, C. et al (1996), J. Cell Biol., 134, 1063-1073]. VCAM-1 expression is upregulated on endothelial cells in vitro by inflammatory cytokines [Osborn, L. et al (1989) Cell, 59, 1203-1211] and in human inflammatory diseases such as rheumatoid arthritis [Morales-Ducret, J. et al (1992). J. Immunol., 149, 1424-1431], multiple sclerosis [Cannella, B. et al., (1995). Ann. Neurol., 37, 424-435), allergic asthma [Fukuda, T. et al (1996), Am. J. Respir. Cell Mol. Biol., 14, 84-94] and atherosclerosis [O""Brien, K. D. et al (1993). J. Clin. Invest., 92, 945-951].
Monoclonal antibodies directed against the xcex14 integrin subunit have been shown to be effective in a number of animal models of human inflammatory diseases including multiple sclerosis, rheumatoid arthritis, allergic asthma, contact dermatitis, transplant rejection, insulin-dependent diabetes, inflammatory bowel disease, and glomerulonephritis.
Integrins recognise short peptide motifs in their ligands The minimal xcex14xcex21 binding epitope in CS-1 is the tripeptide leucine-aspartic acid-valine (Leu-Asp-Val) [Komoriya, A., et al (1991). J. Biol. Chem., 266, 15075-15079] while VCAM-1 contains the similar sequence isoleucine-aspartic acid-serine [Clements, J. M., et al (1994). J. Cell Sci., 107, 2127-2135]. The 25-amino acid fibronectin fragment, CS-1 peptide, which contains the Leu Asp-Val motif, is a competitive inhibitor of xcex14xcex21 binding to VCAM-1 [Makarem, R., et al (1994). J. Biol. Chem., 269, 4005-4011]. Small molecule xcex14xcex21 inhibitors based on the Leu-Asp-Val sequence in CS-1 have been described, for example the linear molecule phenylacetic acid-Leu-Asp-Phe-D-Pro-amide [Molossi, S. et al (1995). J. Clin. Invest., 95, 2601-2610] and the disulphide cyclic peptide Cys-Trp-Leu-Asp-Val-Cys [Vanderslice, P., et al (1997). J. Immunol., 158, 1710-1718].
More recently, non- and semi-peptidic compounds which inhibit xcex14xcex21/VCAM binding and which can be orally administered have been reported in for example, WO96/22966 and WO98/04247.
There remains a continuing need for alternative compounds which inhibit the interaction between VCAM-1 and fibronectin with integrin xcex14xcex21 and, in particular, for compounds which can be administered by an oral route.
We have now found a group of compounds which contain a bicyclic heteroaryl ring system which inhibit this interaction.
Accordingly the present invention provides a compound of formula (I) 
wherein:
A is a bicyclic heteroaryl, optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 alkanoyl, C2-6alkenyl, C2-6alkynyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkylthio, C1-4 alkylsulphonyl, C1-4alkoxylC1-6alkyl, C1-6alkylamino-C1-6alkyl, carboxy, carbamoyl, C2-6 alkenyloxy, C2-6alkynyloxy, di-[(C1-6)alkyl]amino, C2-6alkanoylamino, Nxe2x80x94C1-6alkylcarbamoyl, C1-6alkoxylcarbonyl, halogeno, nitro, cyano, amino trifluoromethyl, trifluoromethoxy, hydroxy, (CH2)pOH where p is 1 or 2, xe2x80x94CO2Ra and xe2x80x94CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl, linked to the nitrogen via a ring carbon atom in one ring and to the group B by a ring carbon atom in the second ring;
B is linker group connecting group A to group D and comprising a 3 or 4 atom linker where each atom is independently selected from carbon, oxygen, nitrogen and sulphur and is optionally substituted with one or more C1-6 alkyl groups or two of such adjacent alkyl substituents may form a ring;
C is aryl or a mono or bicyclic heteroaryl, each of which can be optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-6 alkylthio, C1-4 alkylsulphonyl, C1-4alkoxyl-C1-6alkyl, C1-6alkylaminoC1-6alkyl, carboxy, carbamoyl, C2-6 alkenyloxy, C2-6alkynyloxy, di-[(C1-6)alkyl]amino, C2-6alkanoylamino, Nxe2x80x94C1-6alkylcarbamoyl, C1-6alkoxylcarbonyl, phenoxy, cyano, nitro, amino, halogeno, trifluoromethyl, trifluoromethoxy, hydroxy, (CH2)pOH where p is 1 or 2, xe2x80x94CO2Ra and xe2x80x94CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl, linked to NR1 through a ring carbon atom;
D is an aryl or heteroaryl, both of which are optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-6 alkylthio, C1-4 alkylsulphonyl, C1-4alkoxylC1-4alkyl, C1-6alkylaminoC1-6alkyl, carboxy, carbamoyl, C2-6 alkenyloxy, C2-6alkynyloxy, di-[(C1-6)alkyl]amino, C2-6alkanoylamino, Nxe2x80x94C1-6alkylcarbamoyl, C1-6alkoxylcarbonyl, phenoxy, cyano, nitro, amino, halogeno, trifluoromethyl, trifluoromethoxy, hydroxy, (CH)pOH where p is 1 or 2, xe2x80x94CO2Ra and xe2x80x94CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl;
R1 is hydrogen, C1-5 alkyl, C1-3 alkanoyl or C1-3 alkoxycarbonyl;
R2 to R5 are each independently selected from hydrogen, C1-6 alkyl, aryl and heteroaryl containing up to 2 heteroatoms chosen from oxygen, sulphur and nitrogen, the aryl and heteroaryl optionally substituted with C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-4 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-4alkylC1-6alkyoxyl, C1-6alkylaminoC1-6alkyl, nitro, cyano, halogeno, trifluoromethyl, hydroxy, (CH2)pOH where p is 1 or 2, xe2x80x94CO2Ra, and xe2x80x94CONRaRb, where Ra and Rb are independently selected from hydrogen and C1-6 alkyl or two of R2 to R5 can be taken together to form a 3 to 7 membered ring;
R6 is an acidic functional group;
r and s are each independently 0 or 1 with the proviso that r and s cannot both be 0;
or a pharmaceutically acceptable salt or in vivo hydrolysable derivative thereof.
In this specification the following definitions are adopted:
xe2x80x98Bicyclic heteroarylxe2x80x99 means an aromatic 5,6- 6,5- or 6,6-fused ring system wherein one or both rings contain ring heteroatoms. The ring system may contain up to three heteroatoms, independently selected from oxygen, nitrogen or sulphur and can be optionally substituted with one or more substituents selected from C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-4alkoxylC1-6alkyl, C1-6alkylaminoC1-6alkyl, C1-4 alkylsulphonyl, nitro, cyano, halogeno, trifluoromethyl, trifluoromethoxy, hydroxy, (CH2)pOH where p is 1 or 2, xe2x80x94CO2Ra, and xe2x80x94CONRaRb, where Ra and Rb are independently selected from hydrogen and C1-6 alkyl. When the ring system contains more than one heteroatom at least one heteroatom is nitrogen. Examples of bicyclic heteroaryl""s include quinazolinyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl, phthalazinyl and benzotriazolyl.
xe2x80x98Arylxe2x80x99 typically means phenyl or naphthyl, preferably phenyl.
The 3 to 7 membered ring formed by the substituents R2 to R5 and the 5 to 7 membered ring formed by substituents R7, see below, can be an, optionally substituted, saturated or unsaturated ring, for example phenyl and cyclohexane. However, the ring may contain up to three heteroatoms independently selected from nitrogen, oxygen and sulphur. Examples of suitable ring systems include furanyl, pyrrolinyl, piperidinyl, piperazinyl, pyridyl, imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl, triazinyl, pyridazinyl, pyrazinyl, morpholinyl, tetrahydrofuranyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dihydropyridinyl and tetrahydropyridinyl.
The term xe2x80x98acidic functional groupxe2x80x99 means a group which incorporates an acidic hydrogen and includes carboxylic acids, tetrazoles, acyl sulphonamides, sulphonic and sulphinic acids, and preferably is carboxy.
In this specification suitable specific groups for the substituents mentioned include: for halogeno: fluoro, chloro, bromo and iodo for C1-6alkyl (this includes straight chained, branched structures and ring systems): methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropane and cyclohexane; for C2-6alkenyl: vinyl, allyl and but-2-enyl; for C1-6alkanoyl: formyl, acetyl, propionyl or butyryl; for C2-6alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for C1-6alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for C2-6alkenyloxy: vinyloxy and allyloxy; for C2-4alkynyloxy: ethynyloxy and 2-propynyloxy; for C1-6alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-C1-6alkylamino: dimethylarnino, diethylamino; for C2-6alkanoylamino: acetamido, propionamido and butyramido; for Nxe2x80x94C1-6alkylcarbamoyl N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl; for C1-6alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for C1-4alkoxyC1-6alkyl: methoxymethyl, ethoxymethyl, 1-methoxymethyl, 2-methoxyethyl; for C1-6 alkylthio: methylthio; for C1-4 alkylsulphonyl: methylsulphonyl; for C1-6alkylaminoC1-6alkyl: xe2x80x94CH2NHC2H5 
It will be understood that B excludes those linker groups which are unstable in acid conditions such as those found in the stomach of a human or animal body such as 
Suitably, B is selected from acetamido, 
In one aspect of the invention, A is benzoxazolyl, optionally substituted as hereinbefore defined; B is selected from acetamnido, xe2x80x94C(RcRd)xe2x80x94C(O)xe2x80x94NRexe2x80x94, where Rc, Rd and Re are each independently selected from hydrogen and C1-2 alkyl, and xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94, and most preferably is acetamido; C is phenyl, optionally substituted as hereinbefore defined; s, r and R1 to R6 are as hereinbefore defined.
In a further aspect of the invention the compounds have the formula (II) 
wherein
R1 to R5, s and r are as hereinbefore defined;
each R7 is independently selected from C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-4 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-4alkoxylC1-6alkyl, C1-6alkylaminoC1-6alkyl, cyano, nitro, halogeno, trifluoromethyl, hydroxy, (CH2)pOH where p is 1 or 2, xe2x80x94CO2Ra, and xe2x80x94CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl, or two adjacent substituents can be taken together to form a 5-7 membered ring;
R8 to R14 are independently selected from hydrogen, C1-4 alkyl, C1-4 alkanoyl, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-4 alkoxy, C1-6 alkylamino, C1-4alkoxylC1-6alkyl, C1-6alkylaminoC1-6alkyl, halogeno, nitro, cyano, trifluoromethyl, hydroxy, (CH2)pOH where p is 1 or 2, xe2x80x94CO2Ra, and xe2x80x94CONRaRb, where Ra and Rb are independently hydrogen or C1-6 alkyl;
m is zero or an integer from 1 to 5;
or a pharmaceutically acceptable salt or in vivo hydrolysable derivative thereof.
A particularly suitable class of compounds of formula (II) are those where
R2 and R3 are independently selected from hydrogen or C1-6 alkyl;
R1, R4 and R5 are each hydrogen;
R7 is independently selected from halogeno and C1-6 alkyl, especially methyl;
R8, R9 to R11 and R14 are each hydrogen;
R10 is hydrogen or methoxy;
R12 is C1-6 alkoxy, halogeno or hydrogen
s is zero, m is zero, 1 or 2, and r is 1
or a pharmaceutically acceptable salt or in vivo hydrolysable derivative thereof.
Particularly suitable compounds are those described in the examples.
Some compounds of formula (I) or (II) may possess chiral centres. It is to be understood that the invention encompasses all such optical isomers and diastereoisomers of formula (I) or (II) which inhibit the interaction between VCAM-l and fibronectin with integrin xcex14xcex21.
The activities of the compounds of this invention to inhibit the interaction between VCAM-1 and fibronectin with integrin xcex14xcex21 may be determined using a number of in vitro and in vivo screens.
For example, compounds of formula (I) or (II) preferably have an IC50 of  less than 10 xcexcM, more preferably  less than 1 xcexcM in the MOLTA-4 cell/Fibronectin assay hereinafter described.
In order for it to be used, a compound of formula (I), (II) or a pharmaceutically acceptable salt or an in vivo hydrolysable derivative thereof is typically formulated as a pharmaceutical composition in accordance with standard pharmaceutical practice.
Thus, according to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I) or (II) or a pharmaceutically acceptable salt or an in vivo hydrolysable derivative thereof and a pharmaceutically acceptable carrier.
The pharmaceutical compositions of this invention may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension, or a depot formulation with drug incorporated in a biodegradable polymer. The composition may be in a form suitable for topical administration such as for example creams, ointments and gels. Skin patches are also contemplated. For these purposes, the compositions of this invention may be formulated by means known in the art, such as for example, as described in general terms, in Chapter 25.2 of Comprehensive Medicinal Chemistry, Volume 5, Editor Hansch et al, Pergamon Press 1990.
Furthermore, the pharmaceutical composition of the present invention may contain one or more additional pharmacological agents suitable for treating one or more disease conditions referred to hereinabove in addition to the compounds of the present invention. In a further aspect, the additional pharmacological agent or agents may be co-administered, either simultaneously or sequentially, with the pharmaceutical compositions of the invention.
The composition of the invention will normally be administered to humans such that the daily dose will be 0.01 to 75 mg/kg body weight and preferably 0.1 to 15 mg/kg body weight. A preferred composition of the invention is one suitable for oral administration in unit dosage form for example a tablet or capsule which contains from 1 to 1000 mg and preferably 10 to 500 mg of a compound according to the present invention in each unit dose.
Thus, according to yet another aspect of the invention, there is provided a compound of formula (I) or (II) or a pharmaceutically acceptable salt or an in vivo hydrolysable derivative thereof for use in a method of therapeutic treatment of the human or animal body.
In yet a further aspect of the invention the present invention provides a method of treating a disease mediated by the interaction between VCAM-1 and/or fibronectin and the integrin receptor xcex14xcex21 in need of such treatment which comprises administering to said warm-blooded mammals an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt or an in vivo hydrolysable derivative thereof.
The present invention also provides the use of a compound of formula (I) or (II), a pharmaceutically acceptable salt or an in vivo hydrolysable derivative thereof in the production of a medicament for use in the treatment of a disease or medical condition mediated by the interaction between fibronectin and/or VCAM-1 (especially VCAM-1) and the integrin receptor xcex14xcex21;
In a preferred embodiment the mammal in need of treatment is suffering from multiple sclerosis, rheumatoid arthritis, asthma, coronary artery disease, psoriasis, atherosclerosis, transplant rejection, inflammatory bowel disease, insulin-dependent diabetes and glomerulonephritis.
In another aspect of the invention, there is provided a process for preparing a compound of formula (I), a pharmaceutically acceptable salt or an in vivo hydrolysable derivative thereof which process comprises coupling together, via the formation of an amide bond, a compound of formula (III) 
where L is a leaving group,
and an appropriate amine, where any functional group is optionally protected;
and thereafter, if necessary:
a) removing any protecting group; and
b) forming a pharmaceutically acceptable salt or in vivo hydrolysable derivative.
A particular process for preparing compounds of formula (I) involves coupling together a compound of formula (IV) where R1 and A are as hereinbefore defined and T1 is selected from CH2CO2H, OCH2CO2H and CO2H, and a compound of formula (V) where R2 to R5 are as hereinbefore defined and D has an unprotected CO2H or NH2 with the proviso that when T1 is NH2, D is an unprotected CO2H and when T1 is selected from CH2CO2H, OCH2CO2H, and CO2H, D has an unprotected NH2 and where any other functional group is optionally protected; and thereafter, if necessary:
a) removing any protecting group; and
b) forming a pharmaceutically acceptable salt or in vivo hydrolysable derivative. 
An example of a compound of formula (IV) where A is benzoxazole is a compound of formula (VI) 
where R7, m, R8 to R10 are as hereinbefore defined, and T3 is oxygen or a direct bond and T4 is hydrogen. Compounds of formula (VI) can be prepared as follows starting with o-nitrophenols of the type (formula (VII) T3=CH2.CO2Me) which can be prepared by a variety of methods which include displacement of fluorine in compounds (formula (VII) T3=F and where the hydroxyl is preferably protected) by diethyl sodiomalonate followed by hydrolysis and decarboxylation. Displacement of the fluorine in compounds of the type (formula (VIII); T3=F, T5=Bn) with hydroxide ion gives phenols (formula (VIII) T3=OH T5=Bn) which can be reacted under basic conditions with t-butylbromoacetate to give t-butyl phenoxyacetates. ((formula (VIII) T3=OCH2CO.OtBu, T5=Bn). The benryl protecting group can be removed (e.g. Pd/H2, Pd/ammonium formate or BBr3) to yield a nitro phenol ((formula (VIII) T3=OCH2CO.OtBu, T5=H). Alternatively, Pd mediated coupling with dimethyl malonate of compounds of formula (VIII), (T3=Br, T5=Bn) gives compounds of formula (VIII) (T3=CH2CO2Me, T5=Bn). The benzyl group can be removed as described above to yield a nitro phenol (formula (VIII) T3=CH2CO2Me, T5=H). 
Nitro phenols prepared as above can be reduced to an amino compound (formula (IX) T3=oxygen or direct bond, T4=Me or tBu) using, for example, Pd/H2, Pd/ammonium formate or Fe/HOAc. The amino compounds are unstable and can be converted in situ into the corresponding alkyl 2-phenylaminobenzoxazole-6-acetates (formula (VI) T3=oxygen or direct bond, T4=Me. tBu) using an appropriately 
substituted phenyl isothiocyanate (X) or with an appropriately substituted phenyl dithiocarbamate (XI) in the presence of mercuric oxide. Deprotection of these esters will yield the corresponding acids (formula (VI), T4=H).
Compounds of formula (V) can be prepared as follows. Nitrophenols of formula (XII) where R11, R13 to R14 are as hereinbefore defined on D and R15 is C1-6 alkyl, especially methyl, may be alkylated by appropriately substituted compounds of the formula (XIII) by methods which depend on the nature of T2. If T2=OH the alkylation may be achieved by the Mitsonobu procedure whereas if T2=Br or I alkylation may be achieved by, for example, a base (K2CO3) in acetone or methyl ethyl ketone. The resulting nitro compound may be reduced to the corresponding amine (formula (XIV)) (Pd/H2, Pd/ammonium formate Fe/HOAc) which is an example of a compound of formula (V). 
Compounds represented by formula (VI) (T3=oxygen or direct bond, T4=H) and by formula (XIV) may be coupled by the formation of an amide bond by a variety of methods commonly used in peptide synthesis to yield esters of compounds of formula 1. The reaction of a compound of formula (VI) with a compound of formula (XXV) is performed under standard coupling conditions for forming peptide bonds. They can be performed either on a solid support (Solid Phase Peptide Synthesis) or in solution using normal techniques used in the synthesis of organic compounds. With the exception of the solid support, all the other protecting groups, coupling agents, deblocking reagents and purification techniques are similar in both the solid phase and solution phase peptide synthesis techniques.
During the reaction, amino acid functional groups may, if necessary, be protected by protecting groups, for example Boc (rt-butoxycarbonyl). Such groups can be cleaved when necessary using standard techniques such as acid or base treatment.
Suitable protecting groups for the protection of the acid functional groups include esters.
Coupling reagents for forming peptide bonds include the commonly used azide, symmetrical anhydride, mixed anhydride and various active esters and carbodiimides. In the case of carbodiimides, additives such as 1-hydroxybenzotriazole and N-hydroxysuccinimide may also be added. Other coupling reagents include 1H-benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PBTU), (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU)] and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU).
The coupling reactions can be performed at temperatures between xe2x88x9220xc2x0 C. to 40xc2x0 C. The time of the reaction can vary such as between 10 minutes and 24 hours.
Suitable purification methods for the intermediates and final products include chromatographic techniques such as high pressure liquid chromatography (HPLC) along with many other standard techniques used in organic chemistry (e.g. solvent extraction and crystallisation).
Moieties which do not have an amide bond coupling (i.e. compounds of formula (I) in which B does not include an amide bond) may be coupled by one of several methods of which two are given below. 
Starting with a compound of formula (XV) where R2 to R6, are as hereinbefore defined and R11, R13, R14, R16 and R17 represent substituents on D as hereinbefore defined. A requirement of compounds of formula (XV) is that one of the groups of R11, R13, R14, R16 and R17 will be capable of providing all or part of the link B. When one of these groups is so chosen, the remaining groups must be chosen so that they do not impede or complicate the regiospecificity of the subsequent coupling. Such a group may be bromo, iodo, formyl(xe2x80x94CHO), acyl (R.CO), haloalkyl (particularly halomethyl) and amino. In an example of a compound of formula (XV) where R17 Br, Pd mediated amination (Buchwald) with a protected cyclic amine such as (XVI) can give, after deprotection of the hydroxyl group, compounds of the formula (XVII). 
Coupling, for example under Mitsonubu conditions, of compounds of formula (XVII) with a phenol of formula (XVIII) where R7 and m are as hereinbefore defined (prepared, for example, by the reaction of a thiocarbamate of formula (XIV) with, for example, 4-amino resorcinol hydrochloride and mediated by mercuric oxide) can give compounds according to the invention, such as 
In an example of a compound of formula (XV) where R17=formyl, coupling may be achieved by reductive amination with a compound of formula (XX) T7=an amino function 
e.g. NH2, CH2NH2 and R7, R11 to R13 and m are as hereinbefore defined provide compounds according to the invention. 
It will be appreciated by those skilled in the art that it is possible to incorporate other linker groups by adjusting the group T7 and the group R17.